This invention relates to certain novel analogs of the naturally occurring prostaglandins. In particular, it relates to novel 15-substituted-.omega.-pentanorprostaglandins and various novel intermediates useful in their preparation.
The prostaglandins are C-20 unsaturated fatty acids which exhibit diverse physiological effects. For instance, the prostaglandins of the E and A series are potent vasodilators (Bergstrom et al., Acta Physiol. Scand. 64:332-33 1965 and Bergstrom et al., Life Sci. 6:449-455, 1967) and lower systemic arterial blood pressure (vasodepression) on intravenous administration (Weeks and King, Federation Proc. 23:327, 1964; Bergstrom, et al., 1965 op. cit.; Carlson, et al., Acta Physiol. Scand. 75:161-169, 1969). Another well known physiological action for PGE.sub.1 and PGE.sub.2 is bronchodilation (Cuthbert, Brit. Med. J. 4:723-726, 1969).
Still another important physiological role for the natural prostaglandins is in connection with the reproductive cycle. PGE.sub.2 is known to possess the ability to induce labor (Karim, et al., J. Obstet Gynaec. Brit. Cwlth. 77:200-210, 1970), to induce therapeutic abortion (Bygdeman, et al., Contraception, 4, 293 (1971) and to be useful for control of fertility (Karim, Contraception 3, 173 (1971). Patents have been obtained for several prostaglandins of the E and F series as inducers of labor in mammals (Belgian Patent 754,158 and West German Patent 2,034,641), and on the use of PGF.sub.1, F.sub.2, and F.sub.3 for control of the reproductive cycle (South African Patent 69/6089). It has been shown that luteolysis can take place as a result of administration of PGF.sub.2 .sub..alpha. [Labhsetwar, Nature 230 528 (1971)] and hence prostaglandins have utility for fertility control by a process in which smooth muscle stimulation is not necessary.
Still other known physiological activities for PGE.sub.1 are in the inhibition of gastric acid secretion (Shaw and Ramwell, In: Worcester Symp. on Prostaglandins, New York, Wiley, 1968, p.55-64) and also of platelet aggregation (Emmons, et al., Brit. Med. J. 2:468-472, 1967).
It is now known that such physiological effects will be produced in vivo for only a short period, following the administration of a prostaglandin. A substantial body of evidence indicates that the reason for this rapid cessation of activity is that the natural prostaglandins are quickly and efficiently metabolically deactivated by .beta.-oxidation of the carboxylic acid side-chain and by oxidation of the 15.alpha.-hydroxyl group (Anggard, et al., Acta. Physiol. Scand., 81, 396 (1971) and references cited therein). It has been shown that placing a 15-alkyl group in the prostaglandins has the effect of increasing the duration of action possibly by preventing the oxidation of the C15-hydroxyl [Yankee and Bundy, JACS 94, 3651 (1972) Kirton and Forbes, Prostaglandins, 1, 319 (1972)].
It was, of course, considered desirable to create analogs of the prostaglandins which would have physiological activities equivalent to the natural compounds, but in which the selectivity of action and the duration of the activity would be increased. Increased selectivity of action would be expected to alleviate the severe side effects, particularly gastrointestinal side effects, frequently observed following systemic administration of the natural prostaglandins (Lancet, 536, 1971).
Furthermore, it was considered necessary to produce compounds which could be readily crystallized since the isolation and purification of non-crystalline products is tedious and inefficient.